Mice With Hyperghrelinemia Are Hyperphagic and Glucose Intolerant and Have Reduced Leptin Sensitivity

Department of Investigative Medicine, Hammersmith Campus, Imperial College London, London, UK.
Diabetes (Impact Factor: 8.1). 02/2009; 58(4):840-6. DOI: 10.2337/db08-1428
Source: PubMed


Ghrelin is the only known peripheral hormone to increase ingestive behavior. However, its role in the physiological regulation of energy homeostasis is unclear because deletion of ghrelin or its receptor does not alter food intake or body weight in mice fed a normal chow diet. We hypothesized that overexpression of ghrelin in its physiological tissues would increase food intake and body weight.
We used bacterial artificial chromosome transgenesis to generate a mouse model with increased ghrelin expression and production in the stomach and brain. We investigated the effect of ghrelin overexpression on food intake and body weight. We also measured energy expenditure and determined glucose tolerance, glucose stimulated insulin release, and peripheral insulin sensitivity.
Ghrelin transgenic (Tg) mice exhibited increased circulating bioactive ghrelin, which was associated with hyperphagia, increased energy expenditure, glucose intolerance, decreased glucose stimulated insulin secretion, and reduced leptin sensitivity.
This is the first report of a Tg approach suggesting that ghrelin regulates appetite under normal feeding conditions and provides evidence that ghrelin plays a fundamental role in regulating beta-cell function.

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Available from: Michael Patterson, Jan 28, 2014
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    • "However other laboratories generated Tg mice with increased AG levels. AG or ghrelin analog over-expression exhibited late onset impaired glucose homeostasis despite no changes in body weight [8] [24] [44] [66]. Due to the difficulties to obtain models with high AG levels, some groups developed Tg mice to over-express ghrelin using different strategies. "
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    ABSTRACT: Ghrelin is a pleiotropic and ubiquitous gastric hormone implicated in body physiology. Ghrelin exhibits potent orexigenic actions and increases body weight and adiposity. Ghrelin is also involved in other metabolic functions among which we can highlight the GH releasing activity and the regulation of glucose homeostasis. Ghrelin needs the enzyme GOAT to be acylated, a step essential for binding to the GHSR1a receptor to exert its functions. Genetic animal models emerge as important tools to delineate the physiological relevance of ghrelin on energy balance. Despite the numerous reports using different genetically engineered mouse models targeting the ghelin system, its endogenous relevance in metabolism seems to be less important than its pharmaceutical options. Copyright © 2015. Published by Elsevier Inc.
    Peptides 05/2015; 70:1-6. DOI:10.1016/j.peptides.2015.04.027 · 2.62 Impact Factor
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    • "In contrast, ghrelin knockout mice and GHS-R knockout mice had no changes in either bone mineral content or density in comparison to control mice (106, 107). Transgenic mice over-expressing ghrelin in the brain and stomach showed increased food intake and impaired glucose tolerance but otherwise had normal body size (108). No analysis of bone metabolism was carried out in this study. "
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    ABSTRACT: The positive association between body weight and bone density has been established in numerous laboratory and clinical studies. Apart from the direct effect of soft tissue mass on bone through skeletal loading, a number of cytokines and hormones contribute to the positive association between adipose and bone tissue, acting either locally in sites where cells of the two tissues are adjacent to each other or systemically through the circulation. The current review describes the effects of such local and systemic factors on bone physiology. One class of factors are the adipocyte-secreted peptides (adipokines), which affect bone turnover through a combination of direct effects in bone cells and indirect mechanisms mediated by the central nervous system. Another source of hormones that contribute to the coupling between fat and bone tissue are beta cells of the pancreas. Insulin, amylin, and preptin are co-secreted from pancreatic beta cells in response to increased glucose levels after feeding, and are also found in high circulating levels in obesity. A number of peptide hormones secreted from the gastrointestinal tract in response to feeding affect both fat and bone cells and thus can also act as mediators of the association between the two tissues. The current review focuses on results of laboratory studies investigating possible mechanism involved in the positive association between fat mass and bone mass.
    Frontiers in Endocrinology 05/2014; 5:70. DOI:10.3389/fendo.2014.00070
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    • "These mice showed increased ghrelin expression in brain and increased circulating ghrelin (~5-fold), although they did not differ from wild-type controls in body weight, food intake, energy expenditure or fat mass (Reed et al., 2008). Likewise, Bewick et al. generated a transgenic mouse model overexpressing ghrelin, using a bacterial artificial chromosome containing the ghrelin gene and its promoter (Bewick et al., 2009). These mice exhibited increased circulating ghrelin (~1.5-fold) and increased food intake without long-term body weight gain, perhaps due to a paradoxical increase in energy expenditure (Bewick et al., 2009). "
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    ABSTRACT: Ghrelin is an octanoylated peptide hormone, produced by endocrine cells of the stomach, which acts in the brain to increase food intake and body weight. Our understanding of the mechanisms underlying ghrelin's effects on eating behaviors has been greatly improved by the generation and study of several genetically manipulated mouse models. These models include mice overexpressing ghrelin and also mice with genetic deletion of ghrelin, the ghrelin receptor [the growth hormone secretagogue receptor (GHSR)] or the enzyme that post-translationally modifies ghrelin [ghrelin O-acyltransferase (GOAT)]. In addition, a GHSR-null mouse model in which GHSR transcription is globally blocked but can be cell-specifically reactivated in a Cre recombinase-mediated fashion has been generated. Here, we summarize findings obtained with these genetically manipulated mice, with the aim to highlight the significance of the ghrelin system in the regulation of both homeostatic and hedonic eating, including that occurring in the setting of chronic psychosocial stress.
    Frontiers in Neuroscience 07/2013; 7(7):121. DOI:10.3389/fnins.2013.00121 · 3.66 Impact Factor
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